title: The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line.
abstract: The discovery of a truncated base excision repair pathway in human spermatozoa mediated by OGG1 has raised questions regarding the effect of mutations in critical DNA repair genes on the integrity of the paternal genome. The senescence-accelerated mouse prone 8 (SAMP8) is a mouse model containing a suite of naturally occurring mutations resulting in an accelerated senescence phenotype largely mediated by oxidative stress, which is further enhanced by a mutation in the Ogg1 gene, greatly reducing the ability of the enzyme to excise 8-hydroxy,2'-deoxyguanosine (8OHdG) adducts. An analysis of the reproductive phenotype of the SAMP8 males revealed a high level of DNA damage in caudal epididymal spermatozoa as measured by the alkaline Comet assay. Furthermore, these lesions were confirmed to be oxidative in nature, as demonstrated by significant increases in 8OHdG adduct formation in the SAMP8 testicular tissue (P<0.05) as well as in mature spermatozoa (P<0.001) relative to a control strain (SAMR1). Despite this high level of oxidative DNA damage in spermatozoa, reactive oxygen species generation was not elevated and motility of spermatozoa was found to be similar to that for the control strain with the exception of progressive motility, which exhibited a slight but significant decline with advancing age (P<0.05). When challenged with Fenton reagents (H2O2 and Fe2+), the SAMP8 spermatozoa demonstrated a highly increased susceptibility to formation of 8OHdG adducts compared with the controls (P<0.001). These data highlight the role of oxidative stress and OGG1-dependent base excision repair mechanisms in defining the genetic integrity of mammalian spermatozoa.
authors.affiliation: Reproductive Science Group, School of Environmental and Life Sciences, Priority Research Centre in Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: T B
authors.initials: TB
authors.lastname: Smith
authors.forename: G N
authors.initials: GN
authors.lastname: De Iuliis
authors.forename: T
authors.initials: T
authors.lastname: Lord
authors.forename: R J
authors.initials: RJ
authors.lastname: Aitken
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D004249:DNA Damage / Q000502:physiology; D045647:DNA Glycosylases / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D005298:Fertility / Q000502:physiology; D008297:Male; D051379:Mice; D023421:Models, Animal; D018384:Oxidative Stress / Q000502:physiology*; D010641:Phenotype; D013091:Spermatogenesis / Q000502:physiology; D013094:Spermatozoa / Q000378:metabolism*
chemical_list: D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse